Several attenuated or avirulent members of the Mycobacterium tuberculosis complex, like Mycobacterium bovis BCG (BCG), the vole bacillus. Mycobacterium microti, or the dassie bacillus, are deleted for an overlapping portion of the genome, known as region of difference 1 (RD1) (1-3). This segment is localized close to the origin of replication (4) in all fully virulent members of the complex (5) and harbors genes esxA, coding for the 6 kDa early secreted antigenic target (ESAT-6), and esxB, encoding the 10 kDa culture filtrate protein (CFP-10). The region was recently shown to be required for full virulence of M. tuberculosis (6-8), and when integrated into BCG, improved the ability of the recombinant BCG strain to protect against dissemination of tuberculosis in the mouse- and the guinea pig model (9).
Independent but complementary studies revealed that ESAT-6 and CFP-10 are secreted via the ESAT-6 system-1 (ESX-1), a dedicated secretion apparatus encoded by genes flanking esxA and esxB in the extended RD1 region (9-11). Among the proteins predicted to be involved in this process are a member of the AAA-family of ATPases (Rv3868), which may perform chaperone-like functions by assisting in the assembly and disassembly of protein complexes, and several putative membrane proteins with 1, 3 or 11 transmembrane domains (Rv3869, Rv3870, Rv3877), or ATP binding sites (Rv3871), which could be involved in forming a transmembrane channel for the translocation of the effector molecules.
Although several publications have recently addressed the function of this secretion system (7, 9-14), there is a need in the art for information relating to the effector proteins.